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Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways.

ABSTRACT: Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron-sulfur (Fe-S) cluster synthesis. Heme and Fe-S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways-gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

SUBMITTER: Kitamura N

PROVIDER: S-EPMC8144192 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [II]

Project description:Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

2021-05-24 | GSE161646 | GEO

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [I]

2021-05-24 | GSE161644 | GEO

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [II]

Project description:Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [II]

| PRJNA678987 | ENA

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [I]

Project description:Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways [I]

| PRJNA678988 | ENA

Sema7A protects against high-fat diet-induced obesity and hepatic steatosis by regulating adipo/lipogenesis.

Project description:ObjectiveObesity and related diseases are becoming a growing risk for public health around the world due to the westernized lifestyle. Sema7A, an axonal guidance molecule, has been known to play a role in neurite growth, bone formation, and immune regulation. Whether Sema7A participates in obesity and metabolic diseases is unknown. As several SNPs in SEMA7A and its receptors were found to correlate with BMI and metabolic parameters in the human population, we investigated the potential role of Sema7A in obesity and hepatic steatosis.MethodsGWAS and GEPIA database was used to analyze SNPs in SEMA7A and the correlation of Sema7A expression with lipid metabolism related genes. Sema7A-/- mice and recombinant Sema7A (rSema7A) were used to study the role of Sema7A in HFD-induced obesity and hepatic steatosis. Adipose tissue-derived mesenchymal stem cells (ADSCs) were used to examine the role of Sema7A in adipogenesis, lipogenesis and downstream signaling.ResultsDeletion of Sema7A aggravated HFD-induced obesity. Sema7A deletion enhanced adipogenesis in both subcutaneous and visceral ADSCs, while the addition of rSema7A inhibited adipogenesis of ADSCs and lipogenesis of differentiated mature adipocytes. Sema7A inhibits adipo/lipogenesis potentially through its receptor integrin β1 and downstream FAK signaling. Importantly, administration of rSema7A had protective effects against diet-induced obesity in mice. In addition, deletion of Sema7A led to increased hepatic steatosis and insulin resistance in mice.ConclusionsOur findings reveal a novel inhibitory role of Sema7A in obesity and hepatic steatosis, providing a potential new therapeutic target for obesity and metabolic diseases.

| S-EPMC10009717 | biostudies-literature

Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis.

Project description:The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

| S-EPMC2793052 | biostudies-other

Krill Oil Supplementation Reduces Exacerbated Hepatic Steatosis Induced by Thermoneutral Housing in Mice with Diet-Induced Obesity.

Project description:Preclinical evidence suggests that n-3 fatty acids EPA and DHA (Omega-3) supplemented as phospholipids (PLs) may be more effective than triacylglycerols (TAGs) in reducing hepatic steatosis. To further test the ability of Omega-3 PLs to alleviate liver steatosis, we used a model of exacerbated non-alcoholic fatty liver disease based on high-fat feeding at thermoneutral temperature. Male C57BL/6N mice were fed for 24 weeks a lard-based diet given either alone (LHF) or supplemented with Omega-3 (30 mg/g diet) as PLs (krill oil; ω3PL) or TAGs (Epax 3000TG concentrate; ω3TG), which had a similar total content of EPA and DHA and their ratio. Substantial levels of TAG accumulation (~250 mg/g) but relatively low inflammation/fibrosis levels were achieved in the livers of control LHF mice. Liver steatosis was reduced by >40% in the ω3PL but not ω3TG group, and plasma ALT levels were markedly reduced (by 68%) in ω3PL mice as well. Krill oil administration also improved hepatic insulin sensitivity, and its effects were associated with high plasma adiponectin levels (150% of LHF mice) along with superior bioavailability of EPA, increased content of alkaloids stachydrine and trigonelline, suppression of lipogenic gene expression, and decreased diacylglycerol levels in the liver. This study reveals that in addition to Omega-3 PLs, other constituents of krill oil, such as alkaloids, may contribute to its strong antisteatotic effects in the liver.

| S-EPMC7912192 | biostudies-literature

Dietary γ-Aminobutyric Acid Supplementation Inhibits High-Fat Diet-Induced Hepatic Steatosis via Modulating Gut Microbiota in Broilers.

Project description:The present study aims to investigate the effect of γ-aminobutyric acid (GABA) on liver lipid metabolism and on AA broilers. Broilers were divided into three groups and fed with low-fat diets, high-fat diets, and high-fat diets supplemented with GABA. Results showed that GABA supplementation decreased the level of triglyceride (TG) in the serum and liver of broilers fed high-fat diets, accompanied by up-regulated mRNA expression of genes related to lipolysis and β-oxidation in the liver (p < 0.05). Furthermore, GABA supplementation increased liver antioxidant capacity, accompanied by up-regulated mRNA expression of antioxidant genes (p < 0.05). 16S rRNA gene sequencing showed that GABA improved high-fat diet-induced dysbiosis of gut microbiota, increased the relative abundance of Bacteroidetes phylum and Barnesiella genus, and decreased the relative abundance of Firmicutes phylum and Ruminococcus_torques_group and Romboutsia genus (p < 0.05). Moreover, GABA supplementation promoted the production of propionic acid and butyric acid in cecal contents. Correlation analysis further suggested the ratio of Firmicutes/Bacteroidetes negatively correlated with hepatic TG content, and positively correlated with cecal short chain fatty acids content (r > 0.6, p < 0.01). Together, these data suggest that GABA supplementation can inhibit hepatic TG deposition and steatosis via regulating gut microbiota in broilers.

| S-EPMC9323641 | biostudies-literature

Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

Project description:BackgroundsMitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported.MethodsMice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was utilized to demonstrate underlying molecular mechanism of the effect induced by NHP treatment.ResultsNHP increases mitochondrial biogenesis, improves hepatic steatosis and systematic insulin resistance in high fat diet (HFD) fed mice. NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1α expression. Mechanistically, the activation of AMP-activated protein kinase (AMPK) is involved in NHP induced PGC-1α expression.ConclusionsPGC-1α-mediated mitochondrial biogenesis plays a vital role in the mitigation of hepatic steatosis treated by NHP. Our result suggests that NHP is a good candidate to be dietary supplement for the auxiliary treatment of NAFLD.

| S-EPMC7406515 | biostudies-literature

Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity.

Project description:Mitochondria are the nexus of energy metabolism, and consequently their dysfunction has been implicated in the development of metabolic complications and progression to insulin resistance and type 2 diabetes. The unique tetra-acyl phospholipid cardiolipin (CL) is located in the inner mitochondrial membrane, where it maintains mitochondrial integrity. Here we show that knockdown of Tafazzin (TAZ kd), a CL transacylase, in mice results in protection against the development of obesity, insulin resistance, and hepatic steatosis. We determined that hypermetabolism protected TAZ kd mice from weight gain. Unexpectedly, the large reduction of CL in the heart and skeletal muscle of TAZ kd mice was not mirrored in the liver. As a result, TAZ kd mice exhibited normal hepatic mitochondrial supercomplex formation and elevated hepatic fatty acid oxidation. Collectively, these studies identify a key role for hepatic CL remodeling in regulating susceptibility to insulin resistance and as a novel therapeutic target for diet-induced obesity.

| S-EPMC5079636 | biostudies-literature

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